PROJECT SUMMARY In vivo direct cellular reprogramming has the potential to facilitate the development of highly effective and translational cell therapies for a wide variety of conditions. Current reprogramming methodologies, however, face major practical and translational hurdles, including heavy reliance on viral transfection, and a highly stochastic nature, which often leads to inefficient, unpredictable and unsafe reprogramming outcomes. We developed a novel tissue nano-transfection platform technology that overcomes these barriers by enabling deterministic transduction of reprogramming factors into tissues (with single-cell resolution) without the need for viral vectors. This nanotechnology-based approach promotes remarkably fast and efficient whole tissue reprogramming in vivo. Such platform could be applicable to virtually any cell therapy model, and its non-invasive and non-viral nature make it an ideal intervention approach in a multitude of clinically relevant scenarios. This New Innovator Award Program will seek to further develop this technology and study its implementation in the treatment neurodegenerative disorders at the central and peripheral nervous system levels. Currently, there is no example of non-viral whole tissue reprogramming strategies against neurodegenerative conditions. As such, the work proposed herein is fundamentally innovative and potentially transformative.